The overall long-term objectives of this research are to elucidate mechanisms by which cell surface metalloproteinases and their secreted counterparts are regulated and interact, activate and degrade peptides and proteins at the cell surface and extracellularly, as well as to define the roles of these proteases in health and diseases such as diabetic nephropathy, cancer and inflammatory intestinal disease. The approach has been to identify and characterize proteinases and mechanisms used by living systems to degrade proteins and peptides and to regulate protease action according to the needs of the organism. The work has led to the discovery and characterization of meprins, complex and unique mammalian metalloproteinases abundantly expressed at the brush border membrane of kidney and intestinal epithelial cells. The hypothesis is that meprins are concentrated and localized at the interface between host and exterior environment in the kidney, intestine and at inflammatory sites, and are uniquely structured to act in 'harsh' extracellular environments in host defense. However, during tissue destruction and cell death inappropriate localization and activation of meprins have deleterious effects and these proteases play an active role in pathophysiology of disease. In the next period, it is proposed to: (1) determine the role of meprins in the innate immune system, and specifically in intestinal inflammatory disease, using meprin beta fi null mice to study leukocyte invasion and tissue destruction in models of inflammation, as well as interactions of meprins with bacteria; (2) determine whether meprins are protective against urinary tract infections, whether meprins interact with uropathic bacteria, bacterial pili and U-defensins, and how they affect kidney function in response to ischemia-reperfusion, and (3) determine whether inhibitors of meprins reverse deleterious effects of these proteases in the kidney and intestine in vivo. The availability of the meprin a and knockout mice are unique resources for these studies, and fundamental knowledge of these metalloproteinases will lead to new concepts, methods, treatments, and interventions for inflammatory bowel and kidney and urinary tract diseases.